The Obesity-Associated Peptide Leptin Induces Hypertrophy in Neonatal Rat Ventricular Myocytes

Abstract

One of the major manifestations of obesity is increased production of the adipocyte-derived 16-kDa peptide leptin, which is also elevated in heart disease, including congestive heart failure. However, whether leptin can directly alter the cardiac phenotype is not known. We therefore studied the effect of leptin as a potential hypertrophic factor in cultured myocytes from 1-to 4-day-old neonatal rat heart ventricles. Using RT-PCR, we demonstrate that these cells express the short-form (OB-Ra) leptin receptor. Twenty-four hours of exposure to leptin (0.31 to 31.3 nmol/L) produces a significantly increased cell surface area that peaked at 0.63 nmol/L. Subsequent experiments were done with 3.1 nmol/L leptin, which significantly increased cell area by 42%, protein synthesis by 32%, and ␣-skeletal actin and myosin light chain-2 expression by 250% and 300%, respectively. These events occurred in the absence of any increased cell death. Hypertrophy was preceded by rapid activation of the mitogen-activated protein kinase system including p38 and p44/42 as early as 5 minutes after leptin addition, whereas hypertrophy was inhibited by the p38 inhibitor SB203580 but not by the p44/42 inhibitor PD98059. Our results demonstrate a direct hypertrophic effect of leptin and may offer a biological link between hypertrophy and hyperleptinemic conditions such as obesity.O besity is associated with increased production of leptin, a 16-kDa peptide that is a product of the obesity gene (ob) and produced primarily by adipocytes. 1 The effects of leptin are mediated by distinct receptors (OB-R) belonging to the class I cytokine receptor family. It has been suggested that leptin may contribute to cardiovascular disease, independently of obesity such as in hypertension, 2 where elevated levels of the peptide could be a contributing factor due to its ability to stimulate the sympathetic nervous system. 3 Recent clinical evidence has implicated leptin as a potential independent risk factor for coronary heart disease, 4 and increased plasma leptin levels have been found in patients with congestive heart failure. 5 Heart failure is generally preceded by myocardial remodeling, involving cardiomyocyte hypertrophy and other maladaptive responses, 6 although whether leptin contributes to these events has not been studied. Accordingly, we examined leptin's effects in cultured cardiomyocytes and sought to identify potential mechanisms underlying these effects. Materials and MethodsExperiments were done on primary cultures of rat neonatal cardiomyocytes exposed to leptin for 24 hours in the absence or presence of mitogen-activated protein kinase (MAPK) inhibitors. Hypertrophy was determined by measuring cell area, leucine incorporation, and gene expression of molecular markers. Cell viability was determined by vital staining and MAPK activation with Western blotting.An expanded Materials and Methods section can be found in the online data supplement available at http://www.circresaha.org. ResultsThe leptin receptors are generally classified into two...

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